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Histopathologically, LAM lesions have been described as immature smooth muscle\u2013like cells that are positive for the immature melanocytic marker HMB45\/PMEL\/gp100 and phosphorylated ribosomal protein S6 (pS6). Advances in single-cell sequencing technology allowed us to group LAM cells according to their expression of cancer stem cell (CSC) genes and identify three clusters: a high CSC-like state (i.e., stem-like state), an intermediate state, and a low CSC-like inflammatory state. We show here that, in unique LAM cells, many extracellular matrix (ECM) genes, including collagens and CTHRC1 (collagen triple helix repeat-containing 1), are expressed in the high and intermediate CSC-like LAM clusters and suggest that, as is observed in CSCs, the ECM may provide a shield for LAM lesions against immunosurveillance. In LAM-associated fibroblasts, the bisteric mTORC1-selective inhibitor RMC-5552 blocked translation of TGF-\u03b2 (transforming growth factor-\u03b2)\u2013induced COL1A1, COL6A1, and phosphorylation of the mTORC1 substrates ribosomal protein S6K1\/S6 (S6K1\/ribosomal protein S6) and 4E-BP1\/eIF4E (eukaryotic initiation factor 4E\u2013binding protein\/translation initiation factor 4E), whereas rapamycin, the U.S. Food and Drug Administration\u2013approved therapy for LAM disease, inhibited only the S6K1\/S6 axis. C82, a Wnt\/\u03b2-catenin transcription inhibitor, prevented TGF-\u03b2\u2013induced collagens but not pS6 or p4E-BP1. This demonstrates that mTORC1-driven 4E-BP1\/eIF4E rapamycin-insensitive translational control overrides transcriptional control of ECM genes. Inhibition by RMC-5552 of ECM and fibroblast activation may result in destruction of CSC-like LAM cells and provide more enduring therapy for LAM.<\/jats:p>","DOI":"10.1165\/rcmb.2025-0237oc","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T19:40:47Z","timestamp":1757360447000},"page":"257-270","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":2,"title":["Extracellular Matrix and Fibroblast Activation in Lymphangioleiomyomatosis"],"prefix":"10.1093","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6443-0788","authenticated-orcid":false,"given":"Alexander R","family":"Mukhitov","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine and"},{"name":"Penn-CHOP Lung Biology Institute, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, 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